Project Summary/Abstract The current epidemic of opiate addiction has led to nearly 50 thousand deaths a year in the U.S. Much like the earlier cocaine/crack epidemic, it has proved devastating to individuals, families and communities. The most successful treatment of long-term opiate use disorder (OUD) is still one of maintenance using methadone. This is far from a cure, leaving people functional but still addicted to a narcotic. While the use of powerful opiate blocking drugs, such as naloxone and naltrexone, has demonstrated great value in rescuing victims of opiate overdose, they have proved disappointing in the long term treatment of OUD. The use of these drugs often produces devastating withdrawal symptoms forcing patients to turn to opiates for relief. A better approach to long term OUD treatment is clearly needed. The difficulty in treating OUD stems from the fact that opiate use damages the natural motivational and reward mechanisms in the brain. Curing addiction requires restoring this mechanism. Unfortunately, both opiates and the drugs used to treat OUD, compromise the opiate receptor protein, a key component of the reward mechanism. What is needed is a drug that acts as a switch, blocking the effects of opiates while allowing the reward mechanism to continue to work normally. This requires a new type of drug that operates on the protein control (allosteric) site. The proposal employs high performance computer modeling technology along with biological assays to search for such a drug. If successful it will identify lead compounds that result in drugs that treat and possibly cure opiate addiction.